Browsing by Author "Huang, Jiaoti"
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Item Open Access A pleiotropic ATM variant (rs1800057 C>G) is associated with risk of multiple cancers.(Carcinogenesis, 2021-10-13) Qian, Danwen; Liu, Hongliang; Zhao, Lingling; Luo, Sheng; Walsh, Kyle M; Huang, Jiaoti; Li, Chuan-Yuan; Wei, QingyiATM (ataxia-telangiectasia mutated) is an important cell-cycle checkpoint kinase required for cellular response to DNA damage. Activated by DNA double strand breaks, ATM regulates the activities of many downstream proteins involved in various carcinogenic events. Therefore, ATM or its genetic variants may have a pleiotropic effect in cancer development. We conducted a pleiotropic analysis to evaluate associations between genetic variants of ATM and risk of multiple cancers. With genotyping data extracted from previously published genome-wide association studies of various cancers, we performed multivariate logistic regression analysis, followed by a meta-analysis for each cancer site, to identify cancer risk-associated single-nucleotide polymorphisms (SNPs). In the ASSET two-sided analysis, we found that two ATM SNPs were significantly associated with risk of multiple cancers. One tagging SNP (rs1800057 C>G) was associated with risk of multiple cancers (two-sided P=5.27×10 -7). Because ATM rs1800057 is a missense variant, we also explored the intermediate phenotypes through which this variant may confer risk of multiple cancers and identified a possible immune-mediated effect of this variant. Our findings indicate that genetic variants of ATM may have a pleiotropic effect on cancer risk and thus provide an important insight into common mechanisms of carcinogenesis.Item Open Access Characterization of a castrate-resistant prostate cancer xenograft derived from a patient of West African ancestry.(Prostate cancer and prostatic diseases, 2021-10-13) Patierno, Brendon M; Foo, Wen-Chi; Allen, Tyler; Somarelli, Jason A; Ware, Kathryn E; Gupta, Santosh; Wise, Sandra; Wise, John P; Qin, Xiaodi; Zhang, Dadong; Xu, Lingfan; Li, Yanjing; Chen, Xufeng; Inman, Brant A; McCall, Shannon J; Huang, Jiaoti; Kittles, Rick A; Owzar, Kouros; Gregory, Simon; Armstrong, Andrew J; George, Daniel J; Patierno, Steven R; Hsu, David S; Freedman, Jennifer ABackground
Prostate cancer is a clinically and molecularly heterogeneous disease, with highest incidence and mortality among men of African ancestry. To date, prostate cancer patient-derived xenograft (PCPDX) models to study this disease have been difficult to establish because of limited specimen availability and poor uptake rates in immunodeficient mice. Ancestrally diverse PCPDXs are even more rare, and only six PCPDXs from self-identified African American patients from one institution were recently made available.Methods
In the present study, we established a PCPDX from prostate cancer tissue from a patient of estimated 90% West African ancestry with metastatic castration resistant disease, and characterized this model's pathology, karyotype, hotspot mutations, copy number, gene fusions, gene expression, growth rate in normal and castrated mice, therapeutic response, and experimental metastasis.Results
This PCPDX has a mutation in TP53 and loss of PTEN and RB1. We have documented a 100% take rate in mice after thawing the PCPDX tumor from frozen stock. The PCPDX is castrate- and docetaxel-resistant and cisplatin-sensitive, and has gene expression patterns associated with such drug responses. After tail vein injection, the PCPDX tumor cells can colonize the lungs of mice.Conclusion
This PCPDX, along with others that are established and characterized, will be useful pre-clinically for studying the heterogeneity of prostate cancer biology and testing new therapeutics in models expected to be reflective of the clinical setting.Item Open Access Cistrome analysis of YY1 uncovers a regulatory axis of YY1:BRD2/4-PFKP during tumorigenesis of advanced prostate cancer.(Nucleic acids research, 2021-05) Xu, Chenxi; Tsai, Yi-Hsuan; Galbo, Phillip M; Gong, Weida; Storey, Aaron J; Xu, Yuemei; Byrum, Stephanie D; Xu, Lingfan; Whang, Young E; Parker, Joel S; Mackintosh, Samuel G; Edmondson, Ricky D; Tackett, Alan J; Huang, Jiaoti; Zheng, Deyou; Earp, H Shelton; Wang, Gang Greg; Cai, LingCastration-resistant prostate cancer (CRPC) is a terminal disease and the molecular underpinnings of CRPC development need to be better understood in order to improve its treatment. Here, we report that a transcription factor Yin Yang 1 (YY1) is significantly overexpressed during prostate cancer progression. Functional and cistrome studies of YY1 uncover its roles in promoting prostate oncogenesis in vitro and in vivo, as well as sustaining tumor metabolism including the Warburg effect and mitochondria respiration. Additionally, our integrated genomics and interactome profiling in prostate tumor show that YY1 and bromodomain-containing proteins (BRD2/4) co-occupy a majority of gene-regulatory elements, coactivating downstream targets. Via gene loss-of-function and rescue studies and mutagenesis of YY1-bound cis-elements, we unveil an oncogenic pathway in which YY1 directly binds and activates PFKP, a gene encoding the rate-limiting enzyme for glycolysis, significantly contributing to the YY1-enforced Warburg effect and malignant growth. Altogether, this study supports a master regulator role for YY1 in prostate tumorigenesis and reveals a YY1:BRD2/4-PFKP axis operating in advanced prostate cancer with implications for therapy.Item Open Access Glycans and Glycoconjugates as Biomarkers and Therapeutic Targets for Therapy-Resistant Prostate Cancer(2023) Butler, WilliamProstate Cancer (PCa) is the most common non-cutaneous malignancy and second leading cause of cancer-related mortality in men. Although most men are diagnosed with early-stage disease which is curable through prostatectomy or local radiation, a subset of men develop biochemically recurrent or metastatic disease requiring the use of hormonal therapy. Despite being initially successful, all men treated with hormonal therapy will eventually develop castration-resistant PCa (CRPC) in which the tumor cells are able to actively proliferate and metastasize despite continued androgen receptor (AR) inhibition. Furthermore, ~17-20% of CRPC tumors recur as small cell neuroendocrine carcinoma (SCNC), consisting entirely of AR-negative neuroendocrine (NE) cells which normally only represent 1% of the tumor cell population in the common, adenocarcinoma setting. Based on these observations, there remains an urgent need to discover important molecules in advanced form of PCa that can provide biological insight into CRPC and SCNC, serve as biomarkers for disease subsets, as well as have therapeutic potential. Although many authors have studied changes in the levels of many biomolecules, glycans and glycoconjugates have remained severely understudied due to the complexity of these structures as well as technological limitations. Therefore, the work in this dissertation has explored these structures specifically in the pursuit of developing novel biomarkers and therapeutic targets for advanced forms of PCa and hormone therapy-resistant tumor cells. Furthermore, the information from these studies provides novel information on how tumor glycosylation evolves throughout the evolution of PCa offering new biological insight. Chapter 1 provides a brief overview of PCa, including mechanisms of resistance to hormonal therapy as well as the concept of cellular heterogeneity and its role in disease progression and treatment resistance. Chapter 2 reviews classical and modern studies that have focused on glycans and glycoconjugates and their important role in the progression of PCa. Furthermore, Chapter 2 emphasizes the potential role these structures may serve as both diagnostic and prognostic biomarkers in the context of both tissue and liquid biopsy specimens. Chapter 3 demonstrates the expression of an oncofetal heparan-sulfate proteoglycan, Glypican-3 (GPC3), in NE cells of human PCa, including the highly lethal SCNC variant. Furthermore, Chapter 3 explores the function of GPC3 in NE tumor cells of human PCa as well as its potential molecular mechanism. Chapter 4 explores the utilization of N-glycan imaging mass spectrometry (IMS) to discover N-glycan markers of various stages of PCa progression, including the hormone-naïve, hormonally-treated, hormone-refractory, and NE subsets. Furthermore, the use of several of these discovered N-glycan structures as potential therapeutic targets is discussed as an important future direction to our work. Finally, Chapter 5 provides an outlook on the future exploitation of glycans and glycoconjugates as both biomarkers and therapeutic targets to improve the ability to diagnose clinically-relevant tumors as well as improve treatment options for patients with advanced disease.
Item Open Access Heat shock factor 1 directly regulates transsulfuration pathway to promote prostate cancer proliferation and survival(Communications Biology) Hauck, J Spencer; Moon, David; Jiang, Xue; Wang, Mu-En; Zhao, Yue; Xu, Lingfan; Quang, Holly; Butler, William; Chen, Ming; Macias, Everardo; Gao, Xia; He, Yiping; Huang, JiaotiAbstractThere are limited therapeutic options for patients with advanced prostate cancer (PCa). We previously found that heat shock factor 1 (HSF1) expression is increased in PCa and is an actionable target. In this manuscript, we identify that HSF1 regulates the conversion of homocysteine to cystathionine in the transsulfuration pathway by altering levels of cystathionine-β-synthase (CBS). We find that HSF1 directly binds the CBS gene and upregulates CBS mRNA levels. Targeting CBS decreases PCa growth and induces tumor cell death while benign prostate cells are largely unaffected. Combined inhibition of HSF1 and CBS results in more pronounced inhibition of PCa cell proliferation and reduction of transsulfuration pathway metabolites. Combination of HSF1 and CBS knockout decreases tumor size for a small cell PCa xenograft mouse model. Our study thus provides new insights into the molecular mechanism of HSF1 function and an effective therapeutic strategy against advanced PCa.Item Open Access Lipid nanoparticle-based mRNA vaccines: a new frontier in precision oncology(Precision Clinical Medicine) Jacob, Eden M; Huang, Jiaoti; Chen, MingAbstract The delivery of lipid nanoparticle (LNP)-based mRNA therapeutics has captured the attention of the vaccine research community as an innovative and versatile tool for treating a variety of human malignancies. mRNA vaccines are now in the limelight as an alternative to conventional vaccines owing to their high precision, low-cost, rapid manufacture, and superior safety profile. Multiple mRNA vaccine platforms have been developed to target several types of cancer, and many have demonstrated encouraging results in animal models and human trials. The effectiveness of these new mRNA vaccines depends on the efficacy and stability of the antigen(s) of interest generated and the reliability of their delivery to antigen-presenting cells (APCs), especially dendritic cells (DCs). In this review, we provide a detailed overview of mRNA vaccines and their delivery strategies and consider future directions and challenges in advancing and expanding this promising vaccine platform to widespread therapeutic use against cancer.Item Open Access Molecular determinants for enzalutamide-induced transcription in prostate cancer.(Nucleic acids research, 2019-11) Yuan, Fuwen; Hankey, William; Wu, Dayong; Wang, Hongyan; Somarelli, Jason; Armstrong, Andrew J; Huang, Jiaoti; Chen, Zhong; Wang, QianbenEnzalutamide, a second-generation androgen receptor (AR) antagonist, has demonstrated clinical benefit in men with prostate cancer. However, it only provides a temporary response and modest increase in survival, indicating a rapid evolution of resistance. Previous studies suggest that enzalutamide may function as a partial transcriptional agonist, but the underlying mechanisms for enzalutamide-induced transcription remain poorly understood. Here, we show that enzalutamide stimulates expression of a novel subset of genes distinct from androgen-responsive genes. Treatment of prostate cancer cells with enzalutamide enhances recruitment of pioneer factor GATA2, AR, Mediator subunits MED1 and MED14, and RNA Pol II to regulatory elements of enzalutamide-responsive genes. Mechanistically, GATA2 globally directs enzalutamide-induced transcription by facilitating AR, Mediator and Pol II loading to enzalutamide-responsive gene loci. Importantly, the GATA2 inhibitor K7174 inhibits enzalutamide-induced transcription by decreasing binding of the GATA2/AR/Mediator/Pol II transcriptional complex, contributing to sensitization of prostate cancer cells to enzalutamide treatment. Our findings provide mechanistic insight into the future combination of GATA2 inhibitors and enzalutamide for improved AR-targeted therapy.Item Open Access Molecular Signature to Risk-Stratify Prostate Cancer of Intermediate Risk.(Clin Cancer Res, 2017-01-01) Yin, Yu; Zhang, Qingfu; Zhang, Hong; He, Yiping; Huang, JiaotiA new 30-gene signature has been described that separates prostate cancers of Gleason score ≤6 from those of Gleason score ≥8. It provides independent prognostic information for prostate cancers of intermediate risk (Gleason score of 7), which has the potential to stratify these patients into different risk groups. Clin Cancer Res; 23(1); 6-8. ©2016 AACRSee related article by Sinnott et al., p. 81.Item Open Access Pre-existing Castration-resistant Prostate Cancer-like Cells in Primary Prostate Cancer Promote Resistance to Hormonal Therapy.(European urology, 2022-01-17) Cheng, Qing; Butler, William; Zhou, Yinglu; Zhang, Hong; Tang, Lu; Perkinson, Kathryn; Chen, Xufeng; Jiang, Xiaoyin Sara; McCall, Shannon J; Inman, Brant A; Huang, JiaotiBackground
Hormonal therapy targeting the androgen receptor inhibits prostate cancer (PCa), but the tumor eventually recurs as castration-resistant prostate cancer (CRPC).Objective
To understand the mechanisms by which subclones within early PCa develop into CRPC.Design, setting, and participants
We isolated epithelial cells from fresh human PCa cases, including primary adenocarcinoma, locally recurrent CRPC, and metastatic CRPC, and utilized single-cell RNA sequencing to identify subpopulations destined to become either CRPC-adeno or small cell neuroendocrine carcinoma (SCNC).Outcome measurements and statistical analysis
We revealed dynamic transcriptional reprogramming that promotes disease progression among 23226 epithelial cells using single-cell RNA sequencing, and validated subset-specific progression using immunohistochemistry and large cohorts of publically available genomic data.Results and limitations
We identified a small fraction of highly plastic CRPC-like cells in hormone-naïve early PCa and demonstrated its correlation with biochemical recurrence and distant metastasis, independent of clinical characteristics. We show that progression toward castration resistance was initiated from subtype-specific lineage plasticity and clonal expansion of pre-existing neuroendocrine and CRPC-like cells in early PCa.Conclusions
CRPC-like cells are present early in the development of PCa and are not exclusively the result of acquired evolutionary selection during androgen deprivation therapy. The lethal CRPC and SCNC phenotypes should be targeted earlier in the disease course of patients with PCa.Patient summary
Here, we report the presence of pre-existing castration-resistant prostate cancer (CRPC)-like cells in primary prostate cancer, which represents a novel castration-resistant mechanism different from the adaptation mechanism after androgen deprivation therapy (ADT). Patients whose tumors harbor increased pre-existing neuroendocrine and CRPC-like cells may become rapidly resistant to ADT and may require aggressive early intervention.Item Open Access RB1-deficient prostate tumor growth and metastasis are vulnerable to ferroptosis induction via the E2F/ACSL4 axis.(The Journal of clinical investigation, 2023-03) Wang, Mu-En; Chen, Jiaqi; Lu, Yi; Bawcom, Alyssa R; Wu, Jinjin; Ou, Jianhong; Asara, John M; Armstrong, Andrew J; Wang, Qianben; Li, Lei; Wang, Yuzhuo; Huang, Jiaoti; Chen, MingInactivation of the RB1 tumor suppressor gene is common in several types of therapy-resistant cancers, including metastatic castration-resistant prostate cancer, and predicts poor clinical outcomes. Effective therapeutic strategies against RB1-deficient cancers, however, remain elusive. Here we showed that RB1-loss/E2F activation sensitized cancer cells to ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, by upregulating expression of ACSL4 and enriching ACSL4-dependent arachidonic acid-containing phospholipids, which are key components of ferroptosis execution. ACSL4 appeared to be a direct E2F target gene and was critical to RB1 loss-induced sensitization to ferroptosis. Importantly, using cell line-derived xenografts and genetically engineered tumor models, we demonstrated that induction of ferroptosis in vivo by JKE-1674, a highly selective and stable GPX4 inhibitor, blocked RB1-deficient prostate tumor growth and metastasis and led to improved survival of the mice. Thus, our findings uncover an RB/E2F/ACSL4 molecular axis that governs ferroptosis, and also suggest a promising approach for the treatment of RB1-deficient malignancies.Item Open Access SPOP Promotes Nanog Destruction to Suppress Stem Cell Traits and Prostate Cancer Progression.(Developmental cell, 2019-02) Zhang, Jinfang; Chen, Ming; Zhu, Yasheng; Dai, Xiangpeng; Dang, Fabin; Ren, Junming; Ren, Shancheng; Shulga, Yulia V; Beca, Francisco; Gan, Wenjian; Wu, Fei; Lin, Yu-Min; Zhou, Xiaobo; DeCaprio, James A; Beck, Andrew H; Lu, Kun Ping; Huang, Jiaoti; Zhao, Cheryl; Sun, Yinghao; Gao, Xu; Pandolfi, Pier Paolo; Wei, WenyiFrequent SPOP mutation defines the molecular feature underlying one of seven sub-types of human prostate cancer (PrCa). However, it remains largely elusive how SPOP functions as a tumor suppressor in PrCa. Here, we report that SPOP suppresses stem cell traits of both embryonic stem cells and PrCa cells through promoting Nanog poly-ubiquitination and subsequent degradation. Mechanistically, Nanog, but not other pluripotency-determining factors including Oct4, Sox2, and Klf4, specifically interacts with SPOP via a conservative degron motif. Importantly, cancer-derived mutations in SPOP or at the Nanog-degron (S68Y) disrupt SPOP-mediated destruction of Nanog, leading to elevated cancer stem cell traits and PrCa progression. Notably, we identify the Pin1 oncoprotein as an upstream Nanog regulator that impairs its recognition by SPOP and thereby stabilizes Nanog. Thus, Pin1 inhibitors promote SPOP-mediated destruction of Nanog, which provides the molecular insight and rationale to use Pin1 inhibitor(s) for targeted therapies of PrCa patients with wild-type SPOP.Item Open Access Targeting androgen receptor-independent pathways in therapy-resistant prostate cancer.(Asian journal of urology, 2019-01) Xu, Lingfan; Chen, Junyi; Liu, Weipeng; Liang, Chaozhao; Hu, Hailiang; Huang, JiaotiSince androgen receptor (AR) signaling is critically required for the development of prostate cancer (PCa), targeting AR axis has been the standard treatment of choice for advanced and metastatic PCa. Unfortunately, although the tumor initially responds to the therapy, treatment resistance eventually develops and the disease will progress. It is therefore imperative to identify the mechanisms of therapeutic resistance and novel molecular targets that are independent of AR signaling. Recent advances in pathology, molecular biology, genetics and genomics research have revealed novel AR-independent pathways that contribute to PCa carcinogenesis and progression. They include neuroendocrine differentiation, cell metabolism, DNA damage repair pathways and immune-mediated mechanisms. The development of novel agents targeting the non-AR mechanisms holds great promise to treat PCa that does not respond to AR-targeted therapies.Item Open Access The expanded role of fatty acid metabolism in cancer: new aspects and targets(Precision Clinical Medicine, 2019-10-01) Chen, Ming; Huang, JiaotiAbstract Cancer cells undergo metabolic reprogramming to support cell proliferation, growth, and dissemination. Alterations in lipid metabolism, and specifically the uptake and synthesis of fatty acids (FAs), comprise one well-documented aspect of this reprogramming. Recent studies have revealed an expanded range of roles played by FA in promoting the aggressiveness of cancer while simultaneously identifying new potential targets for cancer therapy. This article provides a brief review of these advances in our understanding of FA metabolism in cancer, highlighting both recent discoveries and the inherent challenges caused by the metabolic plasticity of cancer cells in targeting lipid metabolism for cancer therapy.Item Open Access Therapeutic potential of ReACp53 targeting mutant p53 protein in CRPC.(Prostate cancer and prostatic diseases, 2020-03) Zhang, Yaqun; Xu, Lingfan; Chang, Yan; Li, YanJing; Butler, William; Jin, Er; Wang, Aifen; Tao, Yulei; Chen, Xufeng; Liang, Chaozhao; Huang, JiaotiBACKGROUNDS:p53 is a tumor suppressor that prevents cancer onset and progression, and mutations in the p53 gene cause loss of the tumor suppressor function of the protein. The mutant p53 protein in tumor cells can form aggregates which contribute to the dominant-negative effect over the wild-type p53 protein, causing loss of p53 tumor suppression or gain of novel oncogenic functions. Mutations in p53 have been implicated in the pathogenesis of primary prostate cancer (PCa), and are often detected in recurrent and metastatic disease. Thus, targeting mutant p53 may constitute an alternative therapeutic strategy for advanced PCa for which there are no other viable options. METHODS:In this study, we used immunoprecipitation, immunofluorescence, clonogenic survival, and cell proliferation assays, flow cytometric analysis and in vivo xenograft to investigate the biological effects of ReACp53, a cell-permeable peptide inhibitor of p53 aggregation, on mutant p53-carrying PCa cells. RESULTS:Our results show that ReACp53 targets amyloid aggregates of mutant p53 protein and restores the p53 nuclear function as transcriptional factor, induces mitochondrial cell death and reduces DNA synthesis of mutant p53-carrying PCa cells; ReACp53 also inhibits xenograft tumor growth in vivo. CONCLUSIONS:The data presented here suggest a therapeutic potential of targeting mutant p53 protein in advanced PCa setting, which has a clinical impact for aggressive PCa with transforming how such tumors are managed.Item Open Access Urinary pubic symphysis fistula leads to histopathologic osteomyelitis in prostate cancer survivors(Urology, 2020-08) Kahokehr, Arman A; Boysen, William R; Schild, Michael H; Nosé, Brent D; Huang, Jiaoti; Eward, Will; Peterson, Andrew C